Over the last decade there has been a growing interest in the importance of mechanical stimuli on cell behavior. Passive physical properties (i.e., alignment, stiffness) and actively applied mechanical stimuli (i.e., stretch, fluid shear stress) modulate fundamental aspects of cell function.  However, most mechanobiology studies investigate isolated cells on artificial substrates, which lack the complicated 3D structure and composition of the cellular “niche” found within the native tissue. Using tendons as a model system, I will discuss my efforts to measure tissue mechanics at the cellular length scale and understand the cell response to mechanical stimuli during tendon degeneration and development.  The goals of this work are to identify the causes of tendon pathology, discover novel therapeutic options, and direct the design of biomaterials that can recapitulate the behavior of native tissue.